Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats.
ABSTRACT Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ET(B) receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl salt-resistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na(+) intake (17.8 ± 4 pg/day vs. 112 ± 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na(+) intake (13 ± 2 pg/day vs. 29.8 ± 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na(+) diet was also significantly lower than DR rats on a high-Na(+) diet (31 ± 2.8 pg/mg vs. 70.9 ± 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ET(B) receptor expression compared with DR rats while on a high-Na(+) diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat.
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ABSTRACT: An abnormal L-arginine-nitric oxide axis has been suggested to be relevant to the genesis of salt-sensitive hypertension. In the present study we investigated the activities of three isoforms of nitric oxide synthase (NOS) in the kidney of Dahl salt-sensitive and salt-resistant rats. Five-week-old Dahl Iwai salt-sensitive (n = 9) and salt-resistant (n = 10) rats were maintained on a high salt diet (4% sodium chloride) for 4 weeks. We measured calcium-dependent and calcium-independent NOS activities in each particulate and soluble fraction of kidney by conversion of L-[3H]arginine to L-[3H]citrulline. Systolic blood pressure was elevated significantly (P < .001) in salt-sensitive but not salt-resistant rats. Calcium-dependent NOS activity in the soluble fraction was significantly lower in salt-sensitive rats than in salt-resistant rats (25.8 +/- 9.0 versus 48.2 +/- 19.2 disintegrations per microgram protein, respectively; P < .01). There were no differences in calcium-dependent NOS activity in the particulate fraction and calcium-independent NOS activity in the soluble fraction between groups. Renal norepinephrine content was lower in salt-sensitive rats than in salt-resistant rats (P < .05) and was positively correlated with calcium-dependent NOS activity in the soluble fraction (P < .01). Although no differences in endothelial and inducible-type NOS activity were observed a significant reduction in calcium-dependent NOS activity in the soluble fraction of the kidney of salt-sensitive rats suggests that the decreased neural-type NOS activity may in part be involved in the mechanism of salt-sensitive hypertension, possibly through alterations in renal sympathetic nervous activity and sodium handling.Hypertension 01/1996; 26(6 Pt 2):1030-4. · 6.87 Impact Factor
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ABSTRACT: Endothelin-1 (ET-1) inhibits transport in various nephron segments, and the thick ascending limb of the loop of Henle (TALH) expresses ET-1 receptors. In many tissues, activation of ET(B) receptors stimulates release of NO, and we recently reported that endogenous NO inhibits TALH chloride flux (J(Cl)). However, the relationship between ET-1 and NO in the control of nephron transport has not been extensively studied. We hypothesized that ET-1 decreases NaCl transport by cortical TALHs through activation of ET(B) receptors and release of NO. Exogenous ET-1 (1 nM) decreased J(Cl) from 118.3 +/- 15.0 to 62.7 +/- 13.6 pmol. mm(-1). min(-1) (48.3 +/- 8.2% reduction), whereas removal of ET-1 increased J(Cl) in a separate group of tubules from 87.6 +/- 10.7 to 115.2 +/- 10.3 pmol. mm(-1). min(-1) (34.5 +/- 6.2% increase). To determine whether NO mediates the inhibitory effects of ET-1 on J(Cl), we examined the effect of inhibiting of NO synthase (NOS) with N(G)-nitro-L-arginine methyl ester (L-NAME) on ET-1-induced changes in J(Cl). L-NAME (5 mM) completely prevented the ET-1-induced reduction in J(Cl), whereas D-NAME did not. L-NAME alone had no effect on J(Cl). These data suggest that the effects of ET-1 are mediated by NO. Blockade of ET(B) receptors with BQ-788 prevented the inhibitory effects of 1 nM ET-1. Activation of ET(B) receptors with sarafotoxin S6c mimicked the inhibitory effect of ET-1 on J(Cl) (from 120.7 +/- 12.6 to 75.4 +/- 13.3 pmol. mm(-1). min(-1)). In contrast, ET(A) receptor antagonism with BQ-610 did not prevent ET-1-mediated inhibition of TALH J(Cl) (from 96.5 +/- 10.4 to 69.5 +/- 8.6 pmol. mm(-1). min(-1)). Endothelin increased intracellular calcium from 96.9 +/- 14.0 to 191.4 +/- 11.9 nM, an increase of 110.8 +/- 26.1%. We conclude that exogenous endothelin indirectly decreases TALH J(Cl) by activating ET(B) receptors, increasing intracellular calcium concentration, and stimulating NO release. These data suggest that endothelin acts as a physiological regulator of TALH NO synthesis, thus inhibiting chloride transport and contributing to the natriuretic effects of ET-1 observed in vivo.American journal of physiology. Renal physiology 09/2000; 279(2):F326-33. · 3.61 Impact Factor
Article: Renal endothelin in hypertension.[show abstract] [hide abstract]
ABSTRACT: Due to the potent vasoconstrictor action of endothelin-1 and its synthesis throughout the vasculature and other tissues, most investigators believe that it is an active participant in the pathogenesis of hypertension. However, the autocrine and paracrine nature of the endothelin system has made its role difficult to define. In recent years, it has become apparent that endothelin-1 contributes to the regulation of renal salt and water excretion and that it is a major contributor to the hypertension associated with salt-dependency. Evidence suggests that endothelin-1 within the renal medulla is activated in conditions of salt loading and inhibits reabsorption of sodium in a nitric oxide-dependent manner. Blockade of endothelin A receptors lowers arterial pressure in animal models of salt-dependent hypertension. Furthermore, circulating levels of endothelin-1 are generally higher in African-Americans compared to white Americans as is the prevalence of salt-dependent hypertension. Therefore, it would appear that use of endothelin A-selective receptor antagonists should be targeted to those individuals at risk for salt-dependent hypertension. Blockade of endothelin B receptors would not be desirable because of their important role in eliminating a salt load.Current Opinion in Nephrology and Hypertension 04/2000; 9(2):157-64. · 3.96 Impact Factor